Approximately 246 million adults have diabetes worldwide. This number is expected to grow to 380 million by the year 2025. Physical activity reduces the incidence of diabetes in patients with impaired glucose tolerance but is difficult to maintain. Anti-diabetic agents decrease progression to diabetes but can have adverse cardiovascular effects. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers decrease incident diabetes in clinical trials in patients with cardiovascular disease. An effect of ACE inhibition on incident diabetes was not replicated in patients with impaired fasting glucose in the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication trial. In the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research study, valsartan did not improve cardiovascular mortality even though incident diabetes was reduced. Our recent data suggest that the effect of interruption of the renin-angiotensin-aldosterone system may depend on the extent to which aldosterone is decreased, as aldosterone modulates glucose-stimulated insulin secretion in vivo and in vitro. At the same time, short-term studies funded by this grant over the last four years support the hypothesis that pharmacologic measures to increase cyclic guanosine monophosphate (cGMP) improve glucose homeostasis. We have found that acutely increasing the formation of endogenous nitric oxide increases muscle glucose uptake in humans; however, nitric oxide also decreases vascular tissue plasminogen activator release through a cGMP-independent mechanism. In contrast, three-week treatment with the phosphodiesterase 5 (PDE5) inhibitor tadalafil improves beta cell function in subjects with the metabolic syndrome without altering fibrinolytic balance. PDE5 inhibitors have been approved for the long-term treatment of pulmonary hypertension, improve many biomarkers of endothelial function and appear to be safe in patients at risk for cardiovascular events. Therefore, in this proposal, we test the hypothesis that long-term PDE5 inhibition improves glucose homeostasis in individuals with impaired glucose tolerance by improving beta cell function. Specifically, we will test the hypothesis that 3-month treatment with sildenafil improves glucose-stimulated insulin secretion, as measured using hyperglycemic clamp (Aim 1). Based on prior studies in rodent models, we will also consider the alternative hypothesis that 3-month PDE5 inhibition improves insulin sensitivity, as measured using euglycemic-hyperinsulinemic clamp (Aim 2). We hypothesize that long-term administration of the PDE5 inhibitor sildenafil will improve measures of glucose homeostasis in patients with impaired glucose tolerance, while improving biomarkers of fibrinolysis. With a number of new pharmacological strategies to increase cGMP emerging, these studies could have a major impact on the incidence of diabetes and its associated cardiovascular morbidity.